515MO - A phase I trial of durvalumab (Durv) in combination with olaparib (Ola) and capivasertib (Cap) in patients (pts) with advanced or metastatic cancers (Ca) (MEDIPAC)

Background

Tumor-specific homologous recombination (HR) DNA defects and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway are commonly implicated in tumorigenesis, and preclinical studies have shown synergistic effects of poly (ADP-ribose) polymerase (PARP) with PI3K-AKT inhibitors. Both pathways modulate the tumor immune microenvironment by regulation of tumor-infiltrating lymphocytes and reduction of Treg cells. We hypothesized that triplet combination of immunotherapy with PARP and PI3K-AKT pathway inhibition is tolerable and may demonstrate activity in pts with relevant pathway defects.

Methods

We investigated the safety and tolerability, pharmacodynamics (PD) and antitumor activity of Durv+Ola, with escalating doses of Cap. Pts were enrolled in 3+3 dose escalation design. Durv and Ola were dosed at standard doses of 1500mg once 4-weekly and 300mg BD continuous dosing respectively. Cap was dosed intermittently (4 days on, 3 days off) with 2 week run-in prior to triplet therapy, at dose levels (DL) 1,2 and 3 of 160mg, 200mg and 320mg BD respectively. PD studies included analyses of plasma (n=18) and paired tumor biopsies (n=12).

Results

22 pts were enrolled, 14 were evaluable; median age 66 (range 36-81), median lines of prior therapy 4 (range 1-13). Dose escalation proceeded through DL1 (n=4, 3 evaluable), DL2 (n=8, 6 evaluable) and DL3 (n=10, 5 evaluable). Treatment was tolerable with mainly G1-2 adverse events (AEs). Most frequent G3/4 AEs were anemia (4/22), hyperglycemia (3/22), and raised lipase (3/22). No DLTs were observed at DL1/2; 1 DLT (G4 hyperglycemia) was observed at DL3. 2 pts had dose reductions (DR) at DL3 for Cap due to G3 hyperglycemia, 3 pts required DR for Ola due to G3 anemia (1 at DL1, 2 at DL2). Treg downregulation was associated with >20% decrease in tumor size by RECIST 1.1 in 1 pt each at DL2 and DL3. 1 pt with PIK3CA E545K mutant breast Ca had stable disease (SD) for 5 months, and 1 pt with PTEN loss and BRCA1 mutant breast Ca had SD of 6 months despite prior progression on PARP inhibitor.

Conclusions

Triplet Cap+Ola+Durv is tolerable with evidence of PD and antitumor activity. Dose expansion at cap 200mg and 320mg OD are ongoing.

Clinical trial identification

NCT03772561.

Editorial acknowledgement

NA

Legal entity responsible for the study

National University Hospital.

Funding

National Medical Research Council Singapore, AstraZeneca.

Disclosure

J.S. Lim: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Astrazeneca; Financial Interests, Personal, Advisory Board: DKSH; Financial Interests, Personal, Invited Speaker: DKSH; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Synthon Pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: Taiho Pharmaceuticals. R. Sundar: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Advisory Board: Taiho; Non-Financial Interests, Institutional, Principal Investigator: MSD; Non-Financial Interests, Institutional, Advisory Role: Paxman Coolers. A. Wong: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, Travel: Eisai; Non-Financial Interests, Institutional, Research Grant: Ostuka. R. Soo: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Yuhan; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. S.C. Lee: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: ACT genomics; Financial Interests, Personal, Advisory Board: ACT genomics; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Eisai; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Taiho; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Pfizer; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Karyopharm; Financial Interests, Personal, Other, Conference travel: Amgen; Financial Interests, Personal, Other, Conference travel: Pfizer; Financial Interests, Personal, Other, Conference travel: Novartis; Financial Interests, Personal, Other, Conference travel: Roche; Financial Interests, Personal, Other, Conference travel: ACT genomics. B.C. Goh: Financial Interests, Personal, Advisory Role: Adagene; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Personal, Stocks/Shares: Gilead Sciences; Financial Interests, Personal, Stocks/Shares: Moderna; Non-Financial Interests, Institutional, Other, Pharmaceutical suppoer for investigator initiated trial: BMS; Non-Financial Interests, Institutional, Research Grant: MSD; Non-Financial Interests, Institutional, Other, Pharmaceutical suppoer for investigator initiated trial: Taiho. R. Dent: Financial Interests, Personal, Advisory Board, Ad board/speaker: AstraZeneca; Financial Interests, Personal, Advisory Board, Ad board/speaker: Eisai; Financial Interests, Personal, Advisory Board, Ad board/speaker: MSD; Financial Interests, Personal, Advisory Board, Ad board/speaker: Norvatis; Financial Interests, Personal, Advisory Board, Ad board/speaker: Pfizer; Financial Interests, Personal, Advisory Board, Ad board/speaker: Roche; Financial Interests, Personal, Other, Travel, accomodation and expenses: Eisai; Financial Interests, Personal, Other, Travel, accomodation and expenses: MSD; Financial Interests, Personal, Other, Travel, accomodation and expenses: Pfizer; Financial Interests, Personal, Other, Travel, accomodation and expenses: Roche. G. Schiavon: Financial Interests, Personal, Other, Emplyee: AstraZeneca. A. Foxley: Financial Interests, Personal, Other, Employee: AstraZeneca. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Principal Investigator: Bergen Bio; Financial Interests, Institutional, Principal Investigator: Byondis B.V; Financial Interests, Institutional, Research Grant: Karyopharm Therapeutics; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Principal Investigator: Zeria Pharmaceutical; Non-Financial Interests, Institutional, Product Samples, Research study: AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Research study: Eisai; Non-Financial Interests, Institutional, Product Samples, Research study: MSD. All other authors have declared no conflicts of interest.